Plasmodium falciparum causes the deadliest form of malaria, which is responsible for nearly one million deaths annually. New therapies are urgently needed to treat this disease, due to widespread chloroquine resistance and emerging resistance to artemisinins. P. falciparum possesses an essential metabolic pathway, non- mevalonate isoprenoid biosynthesis (the MEP pathway), which is not present in humans. This pathway is a particularly enticing antimalarial drug target because it is shared by other important human pathogens, including Gram-negative bacteria and Mycobacterium tuberculosis. The long-term goal is to develop new therapies for treatment of P. falciparum malaria. We are targeting the first-dedicated enzyme of the MEP pathway, IspC, and we have progressed from target validation and hit identification to the discovery of a novel class of antima- larial compounds. The objectives of this proposal are to advance our antimalarial hit compounds through lead development and optimization and to provide biological support for their mechanism-of-action. Our objectives will be met through two specific aims: 1) generate an optimized lead molecule through iterative medicinal chemical strategies; 2) establish the cellular mechanism-of-action of our compounds. Our approach is innovative, since we have taken an innovative approach to inhibitor design to identify an IspC inhibitor with highly potent antimalarial activity. The proposd research is significant, because we will progress in development of new, much-needed antimalarial therapies.